ArticleAntimicrobial agents and chemotherapy2009
Probing the differential interactions of quinazolinedione PD 0305970 and quinolones with gyrase and topoisomerase IV.
Article in Antimicrobial agents and chemotherapy, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 62 citations in OpenAlex.
- A Comprehensive Review on Discovery, Development, the Chemistry of Quinolones, and Their Antimicrobial Resistance.Current topics in medicinal chemistry · 2026Review
- Target-Mediated Fluoroquinolone Resistance inACS infectious diseases · 2024Article
- Developments in Non-Intercalating Bacterial Topoisomerase Inhibitors: Allosteric and ATPase Inhibitors of DNA Gyrase and Topoisomerase IV.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Discovery of Quinazoline-2,4(1Molecules (Basel, Switzerland) · 2022Article
- Trapping of the transport-segment DNA by the ATPase domains of a type II topoisomerase.Nature communications · 2018Article
- A new class of antibacterials, the imidazopyrazinones, reveal structural transitions involved in DNA gyrase poisoning and mechanisms of resistance.Nucleic acids research · 2018Article
- Ubiquitous Nature of Fluoroquinolones: The Oscillation between Antibacterial and Anticancer Activities.Antibiotics (Basel, Switzerland) · 2017Review
- Interactions between Quinolones and Bacillus anthracis Gyrase and the Basis of Drug Resistance.Biochemistry · 2017Article
- Exploring the active site of the Streptococcus pneumoniae topoisomerase IV-DNA cleavage complex with novel 7,8-bridged fluoroquinolones.Open biology · 2016Article
- The Current Case of Quinolones: Synthetic Approaches and Antibacterial Activity.Molecules (Basel, Switzerland) · 2016Review
- Fluoroquinolones stimulate the DNA cleavage activity of topoisomerase IV by promoting the binding of Mg(2+) to the second metal binding site.Biochimica et biophysica acta · 2016Article
- Crystal structure and stability of gyrase-fluoroquinolone cleaved complexes from Mycobacterium tuberculosis.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Fluoroquinolone interactions with Mycobacterium tuberculosis gyrase: Enhancing drug activity against wild-type and resistant gyrase.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Protective effect of Qnr on agents other than quinolones that target DNA gyrase.Antimicrobial agents and chemotherapy · 2015Article
- Characterization of the novel DNA gyrase inhibitor AZD0914: low resistance potential and lack of cross-resistance in Neisseria gonorrhoeae.Antimicrobial agents and chemotherapy · 2015Article
- Activity of quinolone CP-115,955 against bacterial and human type II topoisomerases is mediated by different interactions.Biochemistry · 2015Article
- Bypassing fluoroquinolone resistance with quinazolinediones: studies of drug-gyrase-DNA complexes having implications for drug design.ACS chemical biology · 2014Article
- Bacillus anthracis GrlAV96A topoisomerase IV, a quinolone resistance mutation that does not affect the water-metal ion bridge.Antimicrobial agents and chemotherapy · 2014Article
- Role of the water-metal ion bridge in mediating interactions between quinolones and Escherichia coli topoisomerase IV.Biochemistry · 2014Article
- Fluoroquinolone-gyrase-DNA complexes: two modes of drug binding.The Journal of biological chemistry · 2014Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Quinazoline-2,4-diones, such as PD 0305970, are new DNA gyrase and topoisomerase IV (topo IV) inhibitors with potent activity against gram-positive pathogens, including quinolone-resistant isolates. The mechanistic basis of dione activity vis-à-vis quinolones is not understood. We present evidence for Streptococcus pneumoniae gyrase and topo IV that PD 0305970 and quinolones interact differently with the enzyme breakage-reunion and Toprim domains, DNA, and Mg2+-four components that are juxtaposed in the topoisomerase cleavage complex to effect DNA scission. First, PD 0305970 targets primarily gyrase in Streptococcus pneumoniae. However, unlike quinolones, which select predominantly for gyrA (or topo IV parC) mutations in the breakage-reunion domain, unusually the dione selected for novel mutants with alterations that map to a region of the Toprim domain of GyrB (R456H and E474A or E474D) or ParE (D435H and E475A). This "dione resistance-determining region" overlaps the GyrB quinolone resistance-determining region and the region that binds essential Mg2+ ions, each function involving conserved EGDSA and PLRGK motifs. Second, dione-resistant gyrase and topo IV were inhibited by ciprofloxacin, whereas quinolone-resistant enzymes (GyrA S81F and ParC S79F) remained susceptible to PD 0305970. Third, dione-promoted DNA cleavage by gyrase occurred at a distinct repertoire of sites, implying that structural differences with quinolones are sensed at the DNA level. Fourth, unlike the situation with quinolones, the Mg2+ chelator EDTA did not reverse dione-induced gyrase cleavage nor did the dione promote Mg2+-dependent DNA unwinding. It appears that PD 0305970 interacts uniquely to stabilize the cleavage complex of gyrase/topo IV perhaps via an altered orientation directed by the bidentate 3-amino-2,4-dione moiety.
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